Tanios Bekaii-Saab, MD: Regorafenib Dose Adjustments

What are the principle recommendations for dose adjustments in patients like Marie on regorafenib therapy?

The dose adjustments depend on the level of toxicity. For the more severe toxicities, grade 3 and above, typically you want to hold the drug and bring down in dosage. The starting dosage is 160 mg daily given over three weeks with a 1 week break. The next level is 120 mg daily, and then after that is 80 mg. So you adjust the doses as needed to the lower dose level until the toxicities clear. Often times, you have to hold the drug for a week to wait for the toxicities to clear before you restart on the lower dose level, and then try to hit the right dose for that patient.

About 20% of all patients will tolerate the full 160 mg, and the other 80% will probably fall closer to the 120 mg. Very few will end up on the 80 mg and then there are certain patients who will never tolerate the drug. Those are the patients that will not continue on the agent. With the right dose adjustments and following up on the patients within the first few weeks, you should be able to get the patient on the right dose.

Case 1: mCRC

Marie K. is a 61-year-old female from Indianapolis, Indiana, who works as a corporate IT consultant. In July of 2013, she was diagnosed with mCRC after presenting to her PCP with symptoms of abdominal fullness and abnormal bowel movements of several weeks’ duration.

Medical history is notable for hip replacement in 2011, and mild GERD

CT scans of the abdomen and pelvis suggest presence of multiple peritoneal implants with mild ascites

Her initial biopsy showed a well-differentiated adenocarcinoma with molecular testing showed RAS-WT and BRAF- WT disease

She received initial therapy with FOLFIRI and cetuximab, and showed good response after 4 cycles

In March of 2014, she returned to her oncologist for a follow-up, and her CT scan showed evidence of progression, with visceral peritoneal metastases and ascites, as well as increasing CEA levels (40.2 ng/mL); her ECOG performance status at time of progression was 0

She was switched to FOLFOX and bevacizumab, with a good response. She had a marked decrease in CEA levels and improvement in her abdominal ascites after 3 cycles of therapy

In January of 2015, she returned for follow up with symptoms of abdominal fullness, increasing fatigue, and declining performance status (PS 1); PET/CT scan at that time showed marked progression of multiple target lesions.

She began treatment with regorafenib at a dose of 160 mg, but treatment was interrupted for 1 week after she developed moderate fatigue and grade 3 hand-foot skin reaction (HFSR); her liver function tests were within normal limits before and during treatment

Her condition improved, and treatment with regorafenib was re-initiated at a dose of 120 mg

Patient tolerated the reduced dose, with some mild fatigue, through 8 cycles of treatment; her disease remained stable on PET/CT at her 2-, 4-, and 6-month assessments, and performance status improved (PS 0)

She was scheduled to undergo oral surgery (dental implants) in October of 2015, and her treatment was interrupted 2 weeks prior to surgery

She returns for follow up 4 weeks after the procedure, with good wound healing and a PS of 0. Her PET/CT scan shows moderate progression of the peritoneal metastases and several new hepatic lesions. Her CEA has also increased to 27.7 ng/mL. Liver and kidney function remain within normal limits.